Hyperlipidemia is a general term that encompasses diseases and disorders characterized by or associated with elevated levels of lipids and/or lipoproteins in the blood. Hyperlipidemias include hypercholesterolemia, hypertriglyceridemia, combined hyperlipidemia, and elevated lipoprotein a (Lp(a)). A particular prevalent form of hyperlipidemia in many populations is hypercholesterolemia.
Hypercholesterolemia, particularly an increase in low-density lipoprotein (LDL) cholesterol (LDL-C) levels, constitutes a major risk for the development of atherosclerosis and coronary heart disease (CHD) (Sharrett et al., 2001, Circulation 104:1108-1113). Low-density lipoprotein cholesterol is identified as the primary target of cholesterol lowering therapy and is accepted as a valid surrogate therapeutic endpoint. Numerous studies have demonstrated that reducing LDL-C levels reduces the risk of CHD with a strong direct relationship between LDL-C levels and CHD events; for each 1 mmol/L (˜40 mg/dL) reduction in LDL-C, cardiovascular disease (CVD) mortality and morbidity is lowered by 22%. Greater reductions in LDL-C produce greater reduction in events, and comparative data of intensive versus standard statin treatment suggest that the lower the LDL-C level, the greater the benefit in patients at very high cardiovascular (CV) risk.
Familial hypercholesterolemia (FH) is an inherited disorder of lipid metabolism that predisposes a person to premature severe cardiovascular disease (CVD). Defects in at least 3 different genes that code for proteins involved in hepatic clearance of low-density lipoprotein (LDL) cholesterol (LDL-C) can cause FH. Examples of such defects include mutations in the gene coding for the LDL receptor (LDLR) that removes LDL-C from the circulation, and in the gene for apolipoprotein (Apo) B, which is the major protein of the LDL particle. In certain cases of FH, the gene coding for proprotein convertase subtilisin/kexin type 9 (PCSK9), an enzyme involved in degrading the LDLR (gain of function mutation), is mutated. In all cases, FH is characterized by an accumulation of LDL-C in the plasma from birth and subsequent development of tendon xanthomas, xanthelasmas, atheromata, and CVD. FH can be classified as either heterozygous FH (heFH) or homozygous FH (hoFH) depending on whether the individual has a genetic defect in one (heterozygous) or both (homozygous) copies of the implicated gene.
Current LDL-C-lowering medications include statins, cholesterol absorption inhibitors, fibrates, niacin, and bile acid sequestrants. Statins are a commonly prescribed treatment for LDL-C lowering. However, despite the availability of such lipid-lowering therapies, many high-risk patients fail to reach their guideline target LDL-C level (Gitt et al., 2010, Clin Res Cardiol 99(11):723-733). For patients who are still unable to achieve guideline target level for LDL-C, despite available lipid-modifying therapy (LMT), mechanical removal of LDL-C by lipoprotein apheresis (e.g., LDL apheresis) is sometimes prescribed. Lipoprotein apheresis removes apoproteinB100-containing lipoproteins from the blood. It is generally regarded as a last-resort option for patients with progressive cardiovascular disease and persistently elevated LDL-C.
However, LDL apheresis is a costly procedure that is invasive and burdensome for patients. Apheresis, in general, involves the mechanical removal blood from a patient; the blood is subjected to centrifugation, filtration or other separation steps outside the body to remove unwanted constituents and then reintroduced back into the patient. Lipoprotein apheresis acutely lowers the LDL-C concentration by 50-75%, which translates to a time-averaged LDL-C reduction of approximately 30% between apheresis procedures. Typical apheresis processes are characterized by a transient reduction in serum lipoprotein concentration that is followed over time by an almost linear return of lipoprotein levels to the elevated “baseline” level. This oscillating pattern of lipoprotein levels, which is characteristic of lipoprotein apheresis therapies, explains the need for periodic apheresis treatments that are required throughout the lifetime of an individual. Furthermore, because of the sparsity of apheresis centers in many geographical locations, many patients must travel a significant distance for this procedure, which is administered over 3 hours and is typically given every week to every 4 weeks, depending on the patient's LDL-C level and cardiovascular risk. In addition, this procedure may require placement of a shunt for frequent vascular access. Low-density lipoprotein apheresis is generally well tolerated, but may result in hypotension, hypocalcemia, allergic reactions, and an acute decrease in serum protein levels. It has been documented that quality of life (QoL, as determined by questionnaire) was lower in patients undergoing apheresis in addition to lipid-lowering drugs compared to patients treated only with lipid-lowering drugs (Schiel et al., 1995, Int J Artif Organs 18:786-793). Thus, patients who are not at LDL-C goal despite receiving an optimized LMT regimen, and who require apheresis to lower LDL-C, would greatly benefit from alternative LDL-C lowering therapies that are capable of reducing or eliminating the need for apheresis.